Many of the active agents in pharmaceutical and cosmetic preparations comprise oils or are immiscible or insoluble in water. It can be difficult to deliver an effective amount of these active agents in order to provide the desired therapeutic effect, due to their lack of water solubility. It is therefore often desirable to provide such agents in water-based compositions (eg. for oral administration, topical application, intravenous injection, intramuscular injection, subcutaneous injection etc). One of the methods for preparing such compositions is to form an emulsion.
An emulsion is a heterogeneous system consisting of at least two immiscible liquids (such as a water phase and an oil phase), one of which is dispersed in the other in the form of droplets, with continuous and discontinuous phases. The discontinuous phase is referred to variously as the dispersed or internal phase, whereas the phase in which the dispersion occurs is referred to as the continuous or external phase. When water is the continuous phase, the emulsion is referred to as oil-in-water (O/W), and when oil is the continuous phase, the emulsion is referred to as water-in-oil (W/O). O/W emulsions are the most frequently used emulsions. However, W/O emulsions are desirable for many applications and would be more extensively used if problems with instability could be overcome.
Macroemulsions are defined as being formed by high shear mixing and normally having particles of 1 micron to 10 microns in size. Such emulsions are difficult to achieve and possess minimal stability, as the oil and water components separate into distinct phases over time. In addition, the droplet size of the macroemulsion increases with time. Various methods have been developed to stabilize such emulsions, such as the addition of additives such as emulsifiers and finely divided solids.
In contrast, microemulsion systems consisting of oil, water, and appropriate emulsifiers can form spontaneously (i.e. form with minimal agitation) and are therefore thermodynamically stable. This level of thermodynamic stability is highly desirable, but seldom achieved. Microemulsion systems theoretically have an infinite shelf life under normal conditions without separating, in contrast to the limited life of macroemulsions. In addition, the size of the droplets in such microemulsions remains constant and is typically less than 150 nm (in general between 10-50 nm) and the microemulsion has very low oil/water interfacial tension.
Emulsions such as microemulsions are important for the development of new and effective active agent delivery systems that allow water insoluble or sparingly soluble active agents to be provided in aqueous solutions appropriate for human use. The preparation of such microemulsions represents a major technological hurdle for pharmaceutical delivery systems as one must choose materials that are biocompatible, non-toxic, clinically acceptable and form stable microemulsions.
Furthermore, many of the known emulsion formulations suffer from an inability to ensure a controlled and prolonged release of the active agent at the desired site as they have a very short retention time at the tissue to which they are applied, due to being readily washed away or degraded. This inability is particularly undesirable, since most biologically active agents must remain at the desired site for a prolonged period in order to be effective.
In view of the above, there is a need to provide emulsion formulations for delivery of active agents that are multi-purpose and can be applied to, for example, topical or mucosal tissues. Such emulsions should preferentially have high bioadhesion capability to ensure contact for a prolonged time. Further they should preferentially be able to carry a high amount of active agent to the site of application for a controlled and prolonged release to the desired tissue.
Although stable emulsion preparations have been described, these compositions typically require the use of high temperatures to melt all ingredients of the oil phase to uniformly disperse the particles of one phase through the particles of the other one. Microemulsions are usually formed at temperatures in excess of 75° C., typically about 90° C., and the composition is then cooled slowly over a period of hours or days to room temperature in order to create the emulsion. For large batches this is a costly and time consuming procedure. There is also the risk that the emulsions will be overheated resulting, for example, in the degradation of some of the ingredients.
Another method by which stable emulsions may be prepared is via the use of surfactants or emulsifiers. Typically, surfactants and emulsifiers for the preparation of emulsions are selected from the group consisting of hydrophilic surfactants and mixtures thereof. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar lipophilic (hydrophobic) moieties; that is, a surfactant compound must be amphiphilic. An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. It should be appreciated that the HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
A group of compounds that have been successfully used as surfactants in the production of macro- and microemulsions are the block copolymers of ethylene oxide and propylene oxide, the poloxamers. A number of these compounds have the unusual property that they become liquid when chilled, but harden when warmed, a characteristic known as thermo-reversibility. Such thermo-reversibility is useful in pharmaceutical compounding wherever it is desirable to handle a material in a fluid state, but performance is preferably in a gelled or more viscous state. Such compounds can be drawn into a syringe for accurate dose measurement or easily applied from a bottle or squirted from a dispenser when cold. When the poloxamer warms to body temperature (eg. when applied to skin or mucosal surfaces) it thickens to a suitable consistency to facilitate proper inunction and adhesion.
The desired gelling temperature can be regulated by adjusting the concentration of the block copolymer, with the lower copolymer concentrations giving higher gelling temperatures. Concentrations of the copolymer of at least 18% to 20% by weight are needed to produce a composition which exhibits such a transition at commercially or physiologically useful temperatures. However, it has been found that incorporating high concentrations of copolymer causes the composition to become extremely viscous or “gelatinised” and solutions containing 18% to 20% by weight of poloxamer typically have high viscosity even in the “liquid” phase, so that these solutions can not function under conditions where low viscosity, free-flowing is required prior to transition. For this reason, typical copolymer emulsions usually contain less than 10% copolymer.
Active Agents
Active agents are chemical materials or compounds which, when administered to an organism (human or animal, generally human) induce a desired pharmacologic effect. Many of the active agents in pharmaceutical and cosmetic preparations comprise oils or are immiscible or insoluble in water. An example of such an active agent is Tea Tree Oil (TTO).
TTO is isolated by distilling the oil from the stems and leaves of the paperbark tree Melaleuca alternafolia. TTO has medicinal properties including antimicrobial, antiviral, anti-inflammatory and antifungal characteristics. Additionally, TTO provides a soothing sensation when in contact with a person's skin. However, the properties of TTO can only be exploited by formulating delivery systems suitable to the various conditions required. When TTO products, in the form of aqueous creams, are exposed to air, the TTO component oxidates and some of the chemical components can change their characteristics, affecting the medicament's effectiveness and safety. The presence of many of the emulsifying agents used to solubilize TTO in water also inhibit or inactivate the activity of TTO. As a gel suspension, TTO tends to separate from the gel base formula, particularly when the suspension contains concentrations of TTO higher than 2%, a process accentuated by changes in temperature (eg. temperatures over 30° C.) and/or applying physical shear forces, such as kneading the gel suspension.
To deliver an effective amount of TTO, it is desirable to apply the oil in a form that will both remain in contact with the skin for an extended period of time and deliver the highest concentration of TTO possible. Microemulsion formulations are therefore highly desirable as they are thermodynamically stable.
This invention has as its objective the formation of safe and effective pharmaceutical microemulsion delivery systems that can be manufactured without the need for the high temperature preparation. Other aims and aspects of the present invention will be apparent from the following description of the present invention.